Journal
THERANOSTICS
Volume 11, Issue 4, Pages 1721-1731Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.54930
Keywords
dendrimers; gold nanoparticles; HIF-1 alpha siRNA; gene silencing; radiotherapy
Categories
Funding
- National Natural Science Foundation of China [81761148028, 21773026]
- National Key RD Program [2017YFE0196200]
- Science and Technology Commission of Shanghai Municipality [19XD1400100, 19PJD001]
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The developed zwitterionic Au DENPs provide a promising platform for dual-mode endogenously and exogenously sensitized radiotherapy of other tumor types, showing enhanced cytotoxic reactive oxygen species (ROS) generation in vitro and double-strand DNA damage in vivo.
Development of a powerful sensitization system to alleviate radioresistance for enhanced tumor radiotherapy (RT) remains to be explored. Herein, we present a unique dual-mode endogenous and exogenous nanosensitizer based on dendrimer-entrapped gold nanoparticles (Au DENPs) to realize enhanced tumor RT. Methods: Generation 5 poly(amidoamine) dendrimers partially modified with 1,3-propanesultone were used for templated synthesis of Au NPs, and the created zwitterionic Au DENPs were adopted for serum-enhanced delivery of siRNA to lead to the knockdown of hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein and downstream genes to relieve tumor invasion. The Au DENPs/siRNA polyplexes were also used for dual-mode endogenous and exogenous sensitization of tumor RT in vivo. Results: Due to the dual-mode endogenous sensitization through HIF-1 alpha gene silencing and the exogenous sensitization through the existing Au component, enhanced RT of cancer cells in vitro and a tumor model in vivo can be realized, which was confirmed by enhanced cytotoxic reactive oxygen species (ROS) generation in vitro and double-strand DNA damage verified from the gamma-H(2)AX protein expression in tumor cells in vivo. By integrating the advantages of HIF-1 alpha gene silencing-induced downregulation of downstream genes and the dual-mode sensitization-enhanced RT, simultaneous inhibition of primary tumors and metastasis can be readily realized. Conclusions: The developed zwitterionic Au DENPs may be used as a promising platform for dual-mode endogenously and exogenously sensitized RT of other tumor types.
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